The smallpox vaccine was the first, and arguably most successful, vaccine ever put into practice, and it was scratched into the skin of individuals. With the invention of syringes and hypodermic needles, vaccination shifted toward administration directly into the muscle, under the assumption that it is better to get a vaccine straight into the body. But it turns out scientists may have had it right the first time.

A paper published this week in Nature suggests that the most important part of the human immune system actually resides in peripheral tissues, and that vaccination through those tissues may be more effective than traditional vaccination into the muscle.

The finding is “quite remarkable,” said Onur Boyman, an immunologist at the University of Zurich, who was not involved in the current study. The researchers showed that a population of immune cells called resident memory T cells, which are present in parts of the body that are in contact with the environment, such as the skin, gut, and lungs, mediate an immune response far stronger than circulating, or central, memory T cells in the blood stream.

“In the past, people have conducted in vivo experiments that suggest resident memory and circulating memory cells confer comparable protection,” said Boyman, who identified some of the first resident memory T cells in the skin in 2004. “This paper provides a nice step forward in showing that these resident memory cells are indeed more effective against a skin infection as compared to central memory cells."

In 2006, Rachael Clark and Thomas Kupper of Brigham and Women’s Hospital in Boston demonstrated that there is a large pool of resident memory T cells in normal skin that initiates and maintains immune reactions in the absence of T cells from the blood. Last year they showed that similar T cells exist in the lungs. The presence of these cells in our peripheral organs makes sense, said Kupper, because these tissues are the first line of defense against infection. The cells are “ready to fight invaders as soon as the barriers are breached,” he said.

A human T cell

NIAID/NIH

In the current study, Kupper, Clark, and their team pitted resident memory T cells against circulating memory T cells in a heads-up match to determine which type of immune cell provides stronger protection against viral re-infection. The researchers infected mice with vaccinia virus, the core component of the smallpox vaccine, to create three different groups: mice with both circulating memory cells and skin resident memory cells, and mice with either one or the other. Each type of mouse was then challenged again with the virus.

“The resident memory cells won hands down,” said Kupper. “It wasn’t even a contest. They’re much more effective.” The mice with active resident memory T cells cleared the infection in 6 days, whether or not circulating memory T cells were present. The mice with only circulating memory T cells took 20 days to clear the infection, only slightly better than the 25 days it took mice that had never been exposed to the virus.

The team also showed that resident memory T cells reside not only at the site of infection, but spread throughout the entire skin and remain present for at least 6 months. Repeated infections in the skin resulted in higher concentrations of resident memory T cells each time.

“We’re injured and infected through the skin many times during our lives, and we think this leads to the accumulation of populations of T cells that [spread] throughout our skin and stay there for long periods of time,” said Kupper.

If the finding holds up, it means that vaccine trials are targeting the wrong cells in the body, said Kupper. Vaccination through peripheral organs, like the skin, lungs, or GI tract, could be more effective than injecting a vaccine into muscle. “It’s a wake up call that we need to think about these T cells when we’re making vaccines, he said.

The results could also mean that researchers are looking at the wrong cell population when measuring the vaccine’s effectiveness. Traditional vaccine trials measure either antibodies in the bloodstream, produced by B cells, or circulating memory T cells. “We’re missing the population of cells we’re trying to make when we vaccinate,” said Kupper, who last year co-founded a vaccine biotech exploring the delivery of vaccine through the upper layers of the skin.

Using the finding to attempt new routes of vaccination “might be plausible,” said Boyman, but first it will be important to find out how the T cells are retained in the skin and how long they stick around. “Would one need to boost the vaccines, and if so, how frequently?” he asked.

The study also has implications for understanding organ-specific immune diseases like psoriasis, asthma, and multiple sclerosis, which may involve renegade resident memory T cells, said Kupper. “The scientific implications are broad.”

One correction: it was only towards the end that smallpox was scratched into the skin using the bifurcated needle; interestingly enough, in the first part of the eradication campaign, the virus was injected into the skin using a quite sophisticated foot-pedal-powered device (see Donald Henderson's book, http://www.amazon.com/Smallpox....

Otherwise, great article - and it's about time we started making use of the properties of our largest organ of immunity - aka the skin.

One correction: it was only towards the end that smallpox was scratched into the skin using the bifurcated needle; interestingly enough, in the first part of the eradication campaign, the virus was injected into the skin using a quite sophisticated foot-pedal-powered device (see Donald Henderson's book, http://www.amazon.com/Smallpox....

Otherwise, great article - and it's about time we started making use of the properties of our largest organ of immunity - aka the skin.